Sensitivity Of Central Nervous System Research Articles

Enhanced facilitation and diminished inhibition characterizes the pronociceptive endogenous pain modulatory balance of persons living with HIV and chronic pain.

Chronic pain in persons living with HIV (PLWH) may be related to alterations in endogenous pain modulatory processes (e.g., high facilitation and low inhibition of nociception) that promote exaggerated pain responses, known as hyperalgesia, and central nervous system (CNS) sensitization. This observational study examined differences in endogenous pain modulatory processes between 59 PLWH with chronic pain, 51 PLWH without chronic pain, and 50 controls without HIV or chronic pain. Quantitative sensory testing for temporal summation (TS) of mechanical and heat pain as well as conditioned pain modulation (CPM) were used to assess endogenous pain facilitatory and inhibitory processes, respectively. Associations among TS, CPM, and self-reported clinical pain severity were also examined in PLWH with chronic pain. Findings demonstrated significantly greater TS of mechanical and heat pain for PLWH with chronic pain compared to PLWH without chronic pain and controls. CPM effects were present in controls, but not in either PLWH with or without chronic pain. Among PLWH with chronic pain, greater TS of mechanical pain was significantly associated with greater average clinical pain severity. Results of this study suggest that enhanced facilitation and diminished inhibition characterizes the pronociceptive endogenous pain modulatory balance of persons living with HIV and chronic pain.

Use of antiepileptic mood stabilizers in dermatology

Several antiepileptic drugs (AEDs) are approved by the US Food and Drug Administration for the treatment of bipolar disorder (valproic acid, divalproex, lamotrigine, carbamazepine) and some cutaneous neuropathic pain syndromes (carbamazepine, gabapentin, pregabalin). The AEDs may be effective in the management of (1) chronic pruritus, including pruritus due systemic disease, including uremia, neuropathic pain, neuropathic pruritus, and complex cutaneous sensory syndromes, especially where central nervous system (CNS) sensitization plays a role; (2) management of emotional dysregulation and the resultant repetitive self-excoriation or other cutaneous self-injury in patients who repetitively stimulate or manipulate their integument to regulate emotions (prurigo nodularis, lichen simplex chronicus, skin picking disorder, trichotillomania); (3) management of dermatologic clinical manifestations associated with autonomic nervous system activation (hyperhidrosis, urticaria, flushing; these often occur in conjunction with psychiatric disorders with prominent autonomic activation and dysregulation, eg, social anxiety disorder, posttraumatic stress disorder); and (4) when certain anticonvulsants have a direct therapeutic effect (eg, in psoriasis); currently the use of AEDs for such cases is largely experimental. Gabapentin (dosage range 300-3600 mg daily) is the most widely studied AED mood stabilizer in dermatology and is especially effective in situations where CNS sensitization is a mediating factor. Further larger-scale controlled studies of AEDs in dermatology are necessary.

Experimental neuropharmacology of Gelsemium sempervirens: Recent advances and debated issues

Gelsemium sempervirens L. (Gelsemium) is traditionally used for its anxiolytic-like properties and its action mechanism in laboratory models are under scrutiny. Evidence from rodent models was reported suggesting the existence of a high sensitivity of central nervous system to anxiolytic power of Gelsemium extracts and Homeopathic dilutions. In vitro investigation of extremely low doses of this plant extract showed a modulation of gene expression of human neurocytes. These studies were criticized in a few commentaries, generated a debate in literature and were followed by further experimental studies from various laboratories. Toxic doses of Gelsemium cause neurological signs characterized by marked weakness and convulsions, while ultra-low doses or high Homeopathic dilutions counteract seizures induced by lithium and pilocarpine, decrease anxiety after stress and increases the anti-stress allopregnanolone hormone, through glycine receptors. Low (non-Homeopathic) doses of this plant or its alkaloids decrease neuropathic pain and c-Fos expression in mice brain and oxidative stress. Due to the complexity of the matter, several aspects deserve interpretation and the main controversial topics, with a focus on the issues of high dilution pharmacology, are discussed and clarified.

Serum ischemia modified albumin (IMA) levels of patients with bipolar disorder in remission and healthy controls

Oxidative stress might play an important role in neurological and psychiatric diseases due to the central nervous system sensitivity to reactive oxygen species. Aim of this study is to contribute these data about oxidative stress in bipolar disorder, by detecting IMA levels of bipolar disorder patients in remission and also by comparing these results with healthy controls. Study population consisted of 35 outpatients with bipolar disorder, who being in remission. The patients meeting the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition criteria for bipolar disorder I. 36 healthy subjects were included as control group. Serum ischemia modified albumin levels of all participants were determined and the results were compared between these two groups. The age, gender and ischemia modified albumin levels were not significantly different between bipolar disorder patients and healthy controls. Studies focusing on oxidative stress in bipolar disorder have reached controversial results up till now. The many different markers have been investigated to explain the effects of oxidative stress on bipolar disorders, and this might be reason why there are conflicting results. In addition, the past episodes of patients who were in remission during this study are unclear. Further investigations are needed to be carrying out to illustrate possible changes of oxidative balance in psychiatric disorders, including bipolar disorder.

Patellar and Achilles tendinopathies are predominantly peripheral pain states: a blinded case control study of somatosensory and psychological profiles

Study designCase–control design.BackgroundTendinopathy is characterised by pain on tendon loading. In persistent cases of upper limb tendinopathy, it is frequently associated with central nervous system sensitisation, whereas less commonly linked...

Childhood trauma: A factor for increased risk of major depression in psoriatic patients

A history of childhood maltreatment (CM) is an important determinant for understanding the development of psychiatric and physical disorders. CM is associated with sensitization of central nervous system (CNS) that leads to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis [1]. Early life stress is a well-known contributor to major depression [2]. The dysregulation of HPA axis and sympathetic nervous system activity also impact skin. Epidermis shows a high vulnerability to such psychological stressors resulting to increase risk for psoriasis [3]. The current study investigates the association between childhood trauma and major depression, childhood trauma and psoriasis, and also severity of major depression in female and male patients with psoriasis. Sixty-four psoriatic patients (female = 34, mean age = 46.87) were evaluated with the Childhood Trauma Questionnaire (CTQ) for the history of CM and with the MINI International Neuropsychiatric Interview for the diagnosis of major depression. CM was associated with major depression, indexed by a higher CTQ in emotional (χ2(3) = 26.002, P < .0005) and physical abuse scores (χ2(3) = 23.764, P < .0005). CM limited to sexual abuse was associated with higher severity of psoriasis (χ2(3) = 9.81, P < .02). There was no indication of a difference between men and women in severity of major depression (U = 444, P = .304). Our findings highlight the importance of recognizing psychiatric comorbidity, in particular major depression, among psoriatic patients. Depressive disorder with the presence of psoriasis may constitute a separate etiology with a greater contribution of early environment.Disclosure of interestThe author has not supplied his/her declaration of competing interest.

How can precision medicine be applied to temporomandibular disorders and its comorbidities?

The Eighth Scientific Meeting of The TMJ Association, Ltd. was held in Bethesda, Maryland, September 11–13, 2016. As in the past, the meeting was cosponsored by components of the National Institutes of Health with speakers invited to review the state of temporomandibular disorder science and propose recommendations to further progress. The theme of precision medicine, which aims to tailor disease treatment and prevention to match the characteristics of an individual patient (genetic, epigenetic, environmental, lifestyle) underscored the current consensus that temporomandibular disorders are no longer viewed as local conditions of jaw pain and dysfunction. Rather, they represent a complex family of biopsychosocial disorders that can progress to chronic pain, most often accompanied by one or more other chronic pain conditions. Temporomandibular disorders and these comorbidities, called chronic overlapping pain conditions, predominantly or exclusively affect women in their childbearing years and reflect central nervous system sensitization. Presenters at the meeting included leaders in temporomandibular disorder and pain research, temporomandibular disorder patients and advocates, and experts in other fields or in the use of technologies that could facilitate the development of precision medicine approaches in temporomandibular disorders.

Influence of Gender on pain: In Temporomandibular Disorders

<p><span style="font-size: medium;">Most patients with TMD disorders will respond to non-operative therapy involving; control of parafunctional behaviors, exercises to restore good jaw function, and use of analgesics and muscle relaxers during episodes of acute pain and dysfunction. But up to 20% of TMD patients will not respond to these conventional treatments and multiple factors influenced by gender can be responsible for this poor response.</span><span style="font-size: medium;">Prolonged nociception in such patients can lead to the peripheral and central nervous system sensitization, as evidenced by low pain thresholds and temporal summation, routinely encountered in patients with chronic TMD symptoms, but also female patients in general. Tailoring treatment to address these gender –based contributing factors is the challenge that providers must meet for successful management of chronic TMD patients. This chapter evaluates</span><span style="font-family: 'Arial','sans-serif';"><span style="font-size: medium;"> gender as an initiating, predisposing, or perpetuating factor for TMD via the role of sex hormones, muscle activity and parafunctional behaviors, pain perception, and genetics.</span></span></p><p> </p><br clear="all" /><p><span style="font-size: medium;"> </span></p>

Nervous System Sensitization as a Predictor of Outcome in the Treatment of Peripheral Musculoskeletal Conditions: A Systematic Review.

Research suggests that peripheral and central nervous system sensitization can contribute to the overall pain experience in peripheral musculoskeletal (MSK) conditions. It is unclear, however, whether sensitization of the nervous system results in poorer outcomes following the treatment. This systematic review investigated whether nervous system sensitization in peripheral MSK conditions predicts poorer clinical outcomes in response to a surgical or conservative intervention. Four electronic databases were searched to identify the relevant studies. Eligible studies had a prospective design, with a follow-up assessing the outcome in terms of pain or disability. Studies that used baseline indices of nervous system sensitization were included, such as quantitative sensory testing (QST) or questionnaires that measured centrally mediated symptoms. Thirteen studies met the inclusion criteria, of which six were at a high risk of bias. The peripheral MSK conditions investigated were knee and hip osteoarthritis, shoulder pain, and elbow tendinopathy. QST parameters indicative of sensitization (lower electrical pain thresholds, cold hyperalgesia, enhanced temporal summation, lower punctate sharpness thresholds) were associated with negative outcome (more pain or disability) in 5 small exploratory studies. Larger studies that accounted for multiple confounders in design and analysis did not support a predictive relationship between QST parameters and outcome. Two studies used self-report measures to capture comorbid centrally mediated symptoms, and found higher questionnaire scores were independently predictive of more persistent pain following a total joint arthroplasty. This systematic review found insufficient evidence to support an independent predictive relationship between QST measures of nervous system sensitization and treatment outcome. Self-report measures demonstrated better predictive ability. Further high-quality prognostic research is warranted.

Post Dural Puncture Headache in Fibromyalgia after Cesarean Section: A Comparative Cohort Study

Background: Patients of chronic pain syndromes like fibromyalgia (FMS) when subjected to spinal anesthesia are theoretically more liable to post dural puncture headache (PDPH) as they have enhanced central nervous system sensitization and decreased descending inhibition. Objective: The current study aims to verify the incidence and chronicity of PDPH in FMS patients. Study Design: Case control study. Methods: In a comparative control study, 70 fibromyalgia patients were scheduled for an elective cesarean delivery fibromyalgia group or Group 1. Group 2 included 70 women scheduled for elective cesarean delivery who had no history of chronic pain and is used as a control group. Both groups were compared regarding the incidence of development of PDPH in the first postoperative 48 hours and the persistence of PDPH for 7 days or more. Settings: Women’s Health Hospital, Assiut University, antenatal Clinic. Results: The fibromyalgia group reported more PDPH (18 patients, 25.7%) as compared to the control group (10 patients, 14.3%), P < 0.01. PDPH persisted for 7 or more days in 8 patients in the fibromyalgia group (11.4%) while, it persisted in 2.86% of the control patients. PDPH continued for more than 3 months in 2 patients in the fibromyalgia group (2.86%) Limitations: Difficulty in calculating the dose of analgesics as patients with fibromyalgia may use other analgesics due to musculoskeletal pain. Conclusion: Dural puncture increases the incidence of PDPH in fibromyalgia patients in comparison with normal controls without increasing other postoperative side effects. Key Words: Fibromyalgia, cesarean section, post dural puncture headache, spinal anesthesia

(509) The PAST-FM (Pain and Stress Treatment for Fibromyalgia) randomized, controlled trial: main effects of emotional awareness and expression and cognitive-behavioral therapies

Trauma, emotional avoidance, and relational conflict are elevated in fibromyalgia (FM) and other chronic pain conditions, precipitating or augmenting symptoms. Cognitive-behavioral therapy (CBT) is modestly effective for FM, but interventions that target disturbed emotional/relational processes may yield stronger effects. We developed Emotional Awareness and Expression Therapy (EAET) and compared it to CBT and an active, education control condition in a multi-site, randomized, allegiance-controlled trial. Patients with FM (N=230) were randomized to the 3 conditions, which had 8, 90-minute, weekly group sessions. Outcomes were assessed at baseline, post-treatment, and 6-month follow-up. Retention to follow-up (91.3%) was excellent. Multilevel modeling (intent-to-treat) compared conditions on change from baseline to post-treatment and follow-up. For pain severity (primary outcome), only EAET had lower mean levels than controls at post-treatment (but not follow-up). Rates of 50% pain reduction at both post-treatment and follow-up were significantly (2 to 3 times) greater for EAET (17%, 22.8%) than CBT (6.1%, 8.5%) and (marginally) education (7.2%, 11.7%). Only EAET improved cognitive functioning, surpassing CBT and controls at post-treatment, and controls at follow-up. Compared to controls, both EAET and CBT reduced sleep problems and depression at post-treatment, and anxiety at follow-up. No significant treatment effects occurred for fatigue and physical functioning. Overall, 33% of EAET patients reported “very much” or “much” improvement at post-treatment and follow-up, significantly outperforming controls (4.1%, 15.3%); CBT was between the two, surpassing controls only at post-treatment (18.8%). We conclude that directly targeting trauma, emotional avoidance, and relational conflict in FM is more effective than not only an active education control condition but also CBT on key outcomes (pain, cognitive functioning). These data suggest that emotional awareness and expression can be effective for FM and other pain disorders (or patients) where there are significant contributions from central nervous system sensitization / augmentation. Funding: NIH AR057808.

Advances in minimally invasive treatment of hemorrhagic and ischemic stroke.

Advances in minimally invasive treatment of hemorrhagic and ischemic stroke.

Mindful EM

Mindful EM

Gpr17 in AgRP Neurons Regulates Feeding and Sensitivity to Insulin and Leptin.

Hypothalamic neurons expressing agouti-related peptide (AgRP) regulate eating and glucose metabolism. Ablation of FOXO1 in AgRP neurons of mice results in reduced food intake, leanness, improved glucose homeostasis, and increased sensitivity to insulin and leptin. We tentatively identified G-protein–coupled receptor Gpr17 as an effector of FOXO1 orexigenic signals in AgRP neurons. In this study, we generated and characterized AgRP neuron–specific Gpr17 knockout mice (Agrp-Gpr17−/−) to test the hypothesis that Gpr17 regulates appetite, energy expenditure, and metabolism. Agrp-Gpr17−/− mice show reduced food intake, increased relative energy expenditure, and increased satiety, resulting in leanness and reduced body fat. They also show increased central nervous system sensitivity to insulin and leptin and reduced plasma glucose excursions following the administration of glucose or pyruvate. In summary, AgRP neuron–specific Gpr17 knockouts phenocopy FOXO1 knockouts in the same cell type, thus supporting our original hypothesis and providing further impetus to develop Gpr17 antagonists for the treatment of obesity.

Small molecule inhibitors of PSD95-nNOS protein–protein interactions as novel analgesics

Aberrant increases in NMDA receptor (NMDAR) signaling contributes to central nervous system sensitization and chronic pain by activating neuronal nitric oxide synthase (nNOS) and generating nitric oxide (NO). Because the scaffolding protein postsynaptic density 95kDA (PSD95) tethers nNOS to NMDARs, the PSD95-nNOS complex represents a therapeutic target. Small molecule inhibitors IC87201 (EC5O: 23.94 μM) and ZL006 (EC50: 12.88 μM) directly inhibited binding of purified PSD95 and nNOS proteins in AlphaScreen without altering binding of PSD95 to ErbB4. Both PSD95-nNOS inhibitors suppressed glutamate-induced cell death with efficacy comparable to MK-801. IC87201 and ZL006 preferentially suppressed phase 2A pain behavior in the formalin test and suppressed allodynia induced by intraplantar complete Freund's adjuvant administration. IC87201 and ZL006 suppressed mechanical and cold allodynia induced by the chemotherapeutic agent paclitaxel (ED50s: 2.47 and 0.93 mg/kg i.p. for IC87201 and ZL006, respectively). Efficacy of PSD95-nNOS disruptors was similar to MK-801. Motor ataxic effects were induced by MK-801 but not by ZL006 or IC87201. Finally, MK-801 produced hyperalgesia in the tail-flick test whereas IC87201 and ZL006 did not alter basal nociceptive thresholds. Our studies establish the utility of using AlphaScreen and purified protein pairs to establish and quantify disruption of protein–protein interactions. Our results demonstrate previously unrecognized antinociceptive efficacy of ZL006 and establish, using two small molecules, a broad application for PSD95-nNOS inhibitors in treating neuropathic and inflammatory pain. Collectively, our results demonstrate that disrupting PSD95-nNOS protein–protein interactions is effective in attenuating pathological pain without producing unwanted side effects (i.e. motor ataxia) associated with NMDAR antagonists.

The common link between functional somatic syndromes may be central sensitisation

ObjectivesFunctional somatic syndromes are common and disabling conditions that all include chronic pain, and which may be related to central nervous system sensitisation. Here, we address the concept of central sensitisation as a physiological basis for the functional somatic syndromes. MethodsA narrative review of the current literature on central sensitisation and physiological studies in the functional somatic syndromes. ResultsCentral sensitisation may be a common neurophysiological process that is able to explain non-painful as well as painful symptoms in these disorders. Furthermore, central sensitisation may represent an endophenotypic vulnerability to the development of these syndromes that potentially explains why they cluster together. ConclusionsFurther research is needed to verify these findings, including prospective studies and the standardisation of combined methods of investigation in the study of central sensitisation in functional somatic syndromes. In turn, this may lead to new explanatory mechanisms and treatments being evaluated. Our conclusions add to the debate over the nomenclature of these syndromes but importantly also provide an explanation for our patients.

A Comparative Study between the Effect of Combined Local Anesthetic and Low-dose Ketamine with Local Anesthetic on Postoperative Complications after Impacted Third Molar Surgery.

Postoperative pain, swelling and trismus are the most common outcome after third molar surgery. Many methods have been tried to improve postoperative comfort after surgery. Ketamine is a phencyclidine derivative that induces a state of dissociative anesthesia. It is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and has a distinct suppression effect on central nervous system (CNS) sensitization. Ketamine in a subanesthetic dose is set to produce analgesic and anti-inflammatory effect. Sixty patients, between the age group of 18 and 38 years, undergoing the extraction of impacted mandibular third molar, reporting to the department of oral and maxillofacial surgery were included in the study. Patients were divided randomly into two groups: local anesthetic alone (LAA) and local anesthetic and ketamine (LAK). Statistical analysis was performed using the Mann-Whitney U/unpaired--t-test and Wilcoxon signed-rank test. There was a significant difference in mouth opening in the LAA and LAK group in the immediate postoperative period. There was a significant difference between the two groups after 1 hour (LAA: 2.37; LAK: 1.40), and 4 hours (LAA: 2.37; LAK: 1.40). There was a significant difference in terms of facial swelling in the immediate postoperative period and day 1 between the LAA and LAK group. Use of subanesthetic dose of ketamine is not only safe but also valuable in reducing patient morbidity after third molar surgery. Combination of a local anesthetic and subanesthetic dose of ketamine during surgical extraction of third molars provides good postoperative analgesia with less swelling and significantly less trismus.

Neuronal substrates and functional consequences of prenatal cannabis exposure.

Cannabis remains one of the world's most widely used substance of abuse amongst pregnant women. Trends of the last 50years show an increase in popularity in child-bearing women together with a constant increase in cannabis potency. In addition, potent herbal "legal" highs containing synthetic cannabinoids that mimic the effects of cannabis with unknown pharmacological and toxicological effects have gained rapid popularity amongst young adults. Despite the surge in cannabis use during pregnancy, little is known about the neurobiological and psychological consequences in the exposed offspring. In this review, we emphasize the importance of maternal programming, defined as the intrauterine presentation of maternal stimuli to the foetus, in neurodevelopment. In particular, we focus on cannabis-mediated maternal adverse effects, resulting in direct central nervous system alteration or sensitization to late-onset chronic and neuropsychiatric disorders. We compare clinical and preclinical experimental studies on the effects of foetal cannabis exposure until early adulthood, to stress the importance of animal models that permit the fine control of environmental variables and allow the dissection of cannabis-mediated molecular cascades in the developing central nervous system. In sum, we conclude that preclinical experimental models confirm clinical studies and that cannabis exposure evokes significant molecular modifications to neurodevelopmental programs leading to neurophysiological and behavioural abnormalities.

Potential urine and serum biomarkers for patients with bladder pain syndrome/interstitial cystitis.

There is a lack of consensus on the pathophysiology of bladder pain syndrome/interstitial cystitis. The chronic pain symptoms of bladder pain syndrome/interstitial cystitis refractory to local treatment could be a result of central nervous system sensitization and persisting abnormalities in the bladder wall, which activate the afferent sensory system. Evidence also shows that bladder pain syndrome/interstitial cystitis is a heterogeneous syndrome and that the two subtypes, the ulcerative (classic) and non-ulcerative types, represent different disease entities. There is a need for non-invasive markers for the differential diagnoses of the subtypes of bladder pain syndrome/interstitial cystitis, and between bladder pain syndrome/interstitial cystitis and bladder sensory disorders, such as hypersensitive bladder syndrome or overactive bladder. Bladder pain syndrome/interstitial cystitis, but not overactive bladder, involves an aberrant differentiation program in the bladder urothelium that leads to altered synthesis of several proteoglycans, cell adhesion and tight junction proteins, and bacterial defense molecules. These findings have led to the rationale for identifying urinary biomarkers to detect bladder pain syndrome/interstitial cystitis in patients with frequency urgency syndrome. Recently, the markers that have been the focus of the most research are antiproliferative factor, epidermal growth factor, heparin-binding epidermal growth factor, glycosaminoglycans and bladder nitric oxide. In addition, inflammatory proteins in the urine and serum play important roles in the pathogenesis of bladder pain syndrome/interstitial cystitis. The urinary proteome is an easily accessible source of biomarkers for differentiation between inflammatory bladder disorders. Analysis of multiple urinary proteins and serum cytokines could provide a diagnostic basis for bladder pain syndrome/interstitial cystitis, and could be a tool for the differential diagnosis of bladder pain syndrome/interstitial cystitis and other sensory bladder disorders.

Pathogenesis and clinical aspects of pain in patients with osteoporosis

Bone pain is one of the most frequent kinds of chronic pain, mainly in elderly patients. It causes a significant worsening of functional capacity and deterioration in the quality of life in people affected. Mechanisms of pain in osteoporosis are poorly known and often extrapolated by other pathologies or other experimental model. One of principal causes would be a "hyper-remodeling" of bone, that involves osteoclasts activity and pathological modifications of bone innervation. Several studies show that osteoclasts play a significant role in bone pain etiology. Pain in osteoporosis is mainly nociceptive, if it become persistent a sensitization of peripheral and central nervous system can occur, so underlining the transition to a chronic pain syndrome. Central sensitization mechanisms are complex and involve several neuromediators and receptors (Substance P, NMDA, etc.). Most common manifestations of osteoporosis are vertebral compression fractures that cause persistent pain, though to differentiate from pain originating in structures as joint or muscle. First manifestation can be an acute pain due to pathological fracture, those of hip often causes disability. Pain in osteoporosis is an important clinical challenge. Often its complications and consequences on patient quality of life are underestimated with not negligible social implications. A balanced and early multimodal pain therapy including opioids as necessary, even in cases of acute pain, improve the functional capacity of patients and helps to prevent neurological alterations that seems to contribute in significant way in causing irreversible pain chronic syndromes.